Cryptosporidiosis, caused by Cryptosporidium spp., the apicomplexan parasite first described by Tyzzer 100 years ago (Tyzzer, Proc Soc Exp Biol Med 1907; 5:12-3), is amongst the most serious diarrheal diseases of humans and livestock species worldwide. Cryptosporidium is a Category B biothreat pathogen.
Cryptosporidiosis is an important burden on society. Human patients comprise three major groupings. Immunocompromised patients are most severely affected. Cryptosporidiosis is a serious complication of HIV AIDS, causing chronic diarrhea with weight loss and wasting. Infection may spread beyond the intestinal tract to other mucosae (Cama et al., J Infect Dis 2007 September 1; 196(5):684-91). Wider availability of antiretroviral drugs has reduced the threat of opportunistic infections with Cryptosporidium spp., but it remains an important complication of HIV, and especially so in developing countries where antiretroviral drugs are not as available. Other immunocompromised individuals, including cancer, transplant, and chemotherapy patients, are at risk (Sulzyc-Bielicka et al., J Parasitol 2007 June; 93(3):722-4; Hong et al., Pediatr Transplant 2007 February; 11(1):94-100).
Otherwise healthy patients, infected sporadically when exposed to Cryptosporidium contaminated water or fecally-contaminated food, typically develop severe debilitating stomach cramps and diarrhea that is self limiting and usually not fatal (Chappell et al., Am J Trop Med Hyg 1999 January; 60(1):157-64). Serologic studies indicate that approximately 20% of individuals in the US experience cryptosporidial infections in their youth, with much higher incidence, over 80%, in some areas (Kuhls et al., Clin Infect Dis 1994 May; 18(5):731-5; Leach et al., Am J Trop Med Hyg 2000 May; 62(5):656-61). Cryptosporidiosis is a leading cause of “travelers diarrhea” (Roy et al., J Clin Microbiol 2004 July; 42(7):2944-51; Okhuysen, Clin Infect Dis 2001 Jul. 1; 33(1):110-4). Outbreaks have affected child daycare and elder-care centers (Naumova et al., Emerg Infect Dis 2003 April; 9(4):418-25; Diers et al., J Parasitol 1989 August; 75(4):637-8). Large outbreaks have resulted from exposure to contaminated water, both drinking water or recreational water in water parks and swimming pools. Flooding events, such as follow hurricanes and heavy rains, place populations at high risk to exposure to Cryptosporidium from both human and animal fecal contaminated water (Sinigalliano et al., Proc Natl Acad Sci USA 2007 May 22; 104(21):9029-34).
Exposure to cattle can be an occupational risk for C. parvum infection (Gait et al., Vet Rec 2008 Jun. 28; 162(26):843-5). C. hominis and C. parvum are categorized as Category B pathogens because of their ability to cause large outbreaks of debilitating disease, and the very low infective dose (10-100 oocysts) of the highly resistant oocysts in healthy adults (Okhuysen et al., Int J Parasitol 2002 May; 32(5):517-25).
In tropical and developing countries Cryptosporidium spp are a common cause of diarrheal disease, especially among children living in impoverished conditions (Newman et al., Ann Intern Med 1994 Mar. 15; 120(6):500-5; Zu et al., Am J Trop Med Hyg 1994 July; 51(1):1-10; Jacobsen et al., J Health Popul Nutr 2007 December; 25(4):399-405).
In livestock cryptosporidiosis is an economically important disease especially in neonatal ruminants and C. parvum is one of the most common causes of diarrheal disease in calves under one month of age (Santin et al., In: Fayer R, Xiao L, eds. Cryptosporidium and Cryptosporidiosis. 2nd ed. Boca Raton: CRC, 2008). Cattle may become asymptomatic long term shedders of oocysts (Casemore et al., Cryptosporidiosis—Human and Animal Epidemiology. In: Fayer R. et al, ed. Cruptosporidium and Cryptosporidiosis. Boca Raton: CRC Press, 2002. p. 65-92). Cryptosporidiosis can be fatal to calves when accompanied by other enteropathogens, and other economic losses arise from lost productivity, increased labor and veterinary costs (de G et al., Int J Parasitol 1999 August; 29(8):1269-87). Infected animals shed large numbers of C. parvum oocysts and thus serve as a reservoir for direct and indirect infection of humans and other livestock.
Despite the significant disease and economic burden arising from cryptosporidiosis, and the screening of many drug compounds, there are currently no consistently effective drugs available (Abubakar et al., Br J Clin Pharmacol 2007 April; 63(4):387-93; Zardi et al., Chemotherapy 2005 July; 51(4):193-6; Zhu, Biochemistry. In: Fayer R, Xiao L, eds. Cryptosporidium and Cryptosporidiosis. 2nd ed. Boca Raton: CRC, 2008; Stockdale et al., Prophylaxis and Chemotherapy. In: Fayer R, Xiao L, eds. Cryptosporidium and Cryptosporidiosis. 2nd ed. Boca Raton: CRC, 2008). Genome information suggests Cryptosporidium lacks many drug targets found in other apicomplexan parasites (Zhu, 2008, supra).
A broad spectrum antiprotozoal thiazolide drug, Nitazoxanide (Alinia®, Romark), was approved in 2002 (children) and 2005 (adults) for cryptosporidiosis and giardiasis, however Cryptosporidium lacks the enzyme target for this drug and results are mixed (Zhu, supra). Paromomycin (Humatin® Parke Davis), used to treat amebiasis, is not highly effective against cryptosporidiosis in vivo, allowing continued oocyst shedding and occasionally leading to problematic biliary infections (Stockdale et al., supra). The consensus is that a therapy for cryptosporidiosis is still urgently needed (Tzipori et al., Trends Parasitol 2008 April; 24(4):184-9). Treatment now relies heavily on symptomatic and supportive measures, such as rehydration (Abubakar et al., supra).
A large number of potential therapeutic agents have been tested in animal models. A few drugs have been tested in the field for veterinary use. Halofuginone lactate (Halocur®, Intervet) has been approved for use in several European countries. Paromomycin sulphate (Gabbrovet®, Ceva Sante Animale) is only available as an injectable against bacterial infections in a couple of countries for piglets, calves and poultry. There is off-label use against Cryptosporidium and Giardia. These drugs are regarded as suppressive but not curative against Cryptosporidium. 
Therefore, development of an effective therapeutic for cryptosporidium remains a major unresolved medical need. A well tolerated, highly effective drug to be administered orally would provide lifesaving benefit immunocompromised patients, and would provide relief from debilitating diarrhea and minimize spread to other patients. It would provide a means to manage large outbreaks, and in tropical countries would enhance the quality of life for many for whom sequential childhood diseases stunt physical and intellectual development. An effective anticryptosporidial which can be easily administered to young calves would have immediate economic benefits, and would reduce the reservoir for zoonotic infection.